S139: INTERIM ANALYSIS OF A REGISTRATION ENABLING STUDY OF PIVEKIMAB SUNIRINE (PVEK, IMGN632) A CD123-TARGETING ANTIBODY-DRUG CONJUGATE, IN PATIENTS WITH BLASTIC PLASMACYTOID DENDRITIC CELL NEOPLASM (BPDCN)
Authors: Naveen Pemmaraju, Giovanni Martinelli, Pau Montesinos, Luca Mazzarella, Daniel J. Deangelo, Harry Erba, Kendra Sweet, Roland Walter, Eric Deconinck, Ollivier Legrand, Eunice Wang, Ahmed Aribi, Matthew Ulrickson, Giovanni Marconi, Andrew Lane, Hagop Kantarjian, Callum Sloss, Kara Malcolm, Patrick Zweidler-Mckay, Naval Daver
Journal: HemaSphere (2023)

Background: BPDCN is a rare, aggressive hematologic malignancy with skin, lymph node, blood, CNS, and bone marrow (BM) involvement. Overexpression of CD123 (IL-3Rα) is observed on BPDCN blasts but has limited expression on normal tissues. BPDCN currently has 1 approved therapy, tagraxofusp (TAG), with a median age of 68, CR/CRc rate of 57% and mOS of 15.8 mos (n=65; Pemmaraju JCO 2022). Pivekimab sunirine (PVEK, IMGN632) is a first-in-class antibody-drug conjugate (ADC) comprising a high-affinity CD123 antibody, cleavable linker and an indolinobenzodiazepine pseudodimer (IGN) payload. This payload alkylates DNA and causes single strand breaks without crosslinking. Aims: To report an interim analysis of safety and anti-tumor activity data in frontline BPDCN pts and updated data on R/R BPDCN pts. Methods: In this phase 1b/2 study, adults with frontline or R/R BPDCN received PVEK 0.045 mg/kg IV on D1 of a 21-day cycle, as a <30-min outpatient infusion. Results: As of Sep 14, 2022, anti-tumor activity and safety data are available for 58 BPDCN pts (16 frontline, 42 R/R). Median age was 74y (range, 60-80y) for frontline and 69y (range, 19-83y) for R/R pts, with 88% of frontline pts ≥65y. At screening, 76% of pts had skin involvement, 50% had BM involvement and 43% had nodal/visceral disease per PET/CT scan. Half of the frontline BPDCN pts had a prior or concomitant hematologic malignancy, e.g. MDS, CMML. Of the 42 R/R BPDCN pts, 33% had received a SCT and 45% received prior TAG. Median number of PVEK doses received overall was 3 (range 1-19); frontline pts received a median of 5 doses (range 2-19). Response data were available for 16 frontline BPDCN pts. Objective response rate (ORR [CR, CRc, CRh, CRi, PR]) was 81% (13/16) with a composite complete remission (CCR [CR, CRc, CRh, CRi]) of 75% (12/16), with an additional pt achieving a CR post-transplant. BM remissions were reported in 6/6 frontline pts with baseline BM involvement. Four (25%) frontline pts were bridged to alloSCT. Median time to first response was 1.5 mos (0.5-3.7 mos). Median duration of response (DOR) in frontline pts was 10.7 mos (up to 13.3 mos without transplant); 7 pts remain on PVEK. For R/R BPDCN pts, ORR was 31% (13/42), with a CCR of 19% (8/42), including pts who failed intensive chemotherapy and transplant. In pts who received prior TAG, ORR was 26% (5/19) and CCR rate was 16% (3/19). Median DOR in R/R BPDCN pts was 3.1 mos (up to 9.2 mos); 10 pts remain on PVEK. The most common treatment-emergent adverse events (TEAEs) (all Gr [Gr 3+]) in >20% of all pts were peripheral edema (53% [12%]), thrombocytopenia (31% [26%]), infusion-related reactions (26% [5%]), constipation (24% [0%]), fatigue (22% [5%]), nausea (22% [0%]) and neutropenia (22% [21%]). Of pts with peripheral edema, 24 (77%) had Gr 1 or 2 events and none were Gr 4; Gr 3 hypoalbuminemia was reported in 3% of pts. No CLS or CRS events were reported. One frontline pt (6%) experienced Gr 2 infusion-related reaction (IRR). Grade ≥3 ALT/AST/TBILI laboratory elevations were recorded in 5%/2%/0% of pts; 1 pt experienced a DLT (Gr 3 ALT increase). The reported 30-day mortality was 2% (1 pt died due to disease progression) and no treatment-related deaths. One (2%) treatment-related AE (TRAE) led to dose reduction and 2 pts (3%) discontinued PVEK due to a TRAE. Summary/Conclusion: PVEK demonstrates compelling activity in frontline and R/R BPDCN pts, including durable responses in the R/R setting for pts who received prior TAG. PVEK safety was manageable with primarily low-grade IRRs and edema and no new safety signals were observed. Enrollment continues in the pivotal de novo frontline BPDCN cohort (NCT03386513)Keywords: Antibody targeting, Monoclonal antibody, Myeloid malignancies